Influenza is a leading cause of death and illness and affects the upper and lower respiratory tracts. There are three types of influenza viruses, influenza A, B and C. Human influenza A and B viruses cause seasonal epidemics of disease. Influenza type C infections cause a mild respiratory illness and are not thought to cause epidemics. Influenza A viruses are divided into subtypes based on two proteins on the surface of the virus: the hemagglutinin (H) and the neuraminidase (N). There are 17 different hemagglutinin subtypes and 10 different neuraminidase subtypes. Influenza A viruses can be further broken down into different strains. Current subtypes of influenza A viruses commonly found in people are influenza A (H1N1) and influenza A (H3N2) viruses. Influenza B viruses are not divided into subtypes, but are classified into two different lineages: B/Victoria/2/87-like and B/Yamagata/16/88-like. Influenza A (e.g. H1N1), A (e.g. H3N2), and influenza B viruses are included in each year's influenza vaccine.
At varying frequencies, five kinds of clinically relevant influenza viruses are circulating in the human population at the present time, three of influenza A and also two of influenza B. Influenza A type virus is divided into two distinct phylogenetic groups 1 and 2. Group 1 includes hemagglutinin subtypes H1, H2, H5, H6, H8, H9, H11, H13 and H16. Group 2 includes H3, H4, H7, H10, H15 and H14. Currently relevant circulating influenza A viruses of group 1 are of subtype H1, which is further divided into those of human and swine origin, and group 2 relevant circulating viruses are presently of subtype H3. Influenza A viruses are responsible for the bulk of seasonal disease, with H3 viruses dominating eight of the past twelve influenza seasons in the United States (CDC Seasonal flu; United States Surveillance Data). In 1968, an H3 virus caused one of the three major influenza pandemics of the twentieth century and H3 viruses have persisted since that time as a significant agent of human disease. In addition to humans, H3 influenza viruses commonly infect birds, swine, and horses. Influenza B viruses have been circulating in humans for more than 100 years, with current strains divided into two lineages, the Yamagata lineage and Victoria lineage. Recently the trivalent influenza vaccine has expanded to a quadrivalent antigen-containing vaccine covering both lineages of influenza B, as well as an H1 virus and H3 virus.
Current prevention and treatments for influenza are not adequate and can be ineffective. Despite widespread vaccination, susceptibility to influenza remains. The factors contributing to susceptibility include (1) incomplete vaccination coverage such as with the 2009 H1N1 pandemic, when vaccine shortages were widespread, (2) years such as 2008 when the vaccine formulation poorly represented the strains in circulation, (3) reduced efficacy of vaccination in the elderly, as the average efficacy ranges from 40-50% at age 65, and only 15-30% past age 70, and (4) the emergence of pandemic strains not represented in seasonal vaccines, with H5N1 being of particular concern. Further, drug resistance against the anti-viral therapeutics currently available for the treatment of influenza has become a serious problem. Resistance to adamantanes (amantidine and rimantadine), drugs that act on the M2 protein and inhibit viral fusion, increased from 1.9% in 2004 to 14.5% during the first 6 months of the 2004-2005 flu season, and currently has surpassed 90% (Sheu, T. G. et al (2011) J Infect Dis 203:13-17). Resistance to oseltamivir phosphate (Tamiflu®), an antiviral drug that inhibits the influenza neuraminidase protein, dramatically increased from 1-2% of H1N1 viruses during the 2006-2007 flu season, to 12% by 2007-2008, and exceeded 99% of the seasonal H1N1 viruses in 2009. Fortunately, the pandemic H1N1 strain of 2009 was sensitive to Tamiflu which likely resulted in fewer deaths. As such there is an overwhelming need for new influenza prophylactic/therapeutic approaches.
Unfortunately, diagnostics to determine flu strain typically require a 12-24 hour turnaround time which results in an unfavorable delay in treatment if determination of strain is needed for selecting the appropriate therapy. Thus there remains a need for antibodies that bind multiple clades and show enhanced affinity thereto. In particular, a passive vaccine that comprises antibodies effective against both influenza A and influenza B and is broadly immunoreactive with multiple strains is desirable in order to avoid the need to characterize an infective virus in detail prior to administering the antibody or antibody mixture. Broadly reactive antibodies and compositions effective against all strains of both influenza A and B are desirable, particularly because prior strain diagnosis is not necessary prior to treatment. High potency is further desirable to facilitate both manufacturing and administration of the agents.